Genetic Variant NM_001369.3:c.5272-17_5272-15dupTTT (chr5-13841918-C-CAAA) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_001369.3(DNAH5):c.5272-17_5272-15dupTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0080 ( 12 hom., cov: 0)

Exomes 𝑓: 0.0019 ( 0 hom. )

Consequence

DNAH5
NM_001369.3 intron

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.617

Publications

0 publications found

Variant links:

Genes affected

DNAH5 (HGNC:2950): (dynein axonemal heavy chain 5) This gene encodes a dynein protein, which is part of a microtubule-associated motor protein complex consisting of heavy, light, and intermediate chains. This protein is an axonemal heavy chain dynein. It functions as a force-generating protein with ATPase activity, whereby the release of ADP is thought to produce the force-producing power stroke. Mutations in this gene cause primary ciliary dyskinesia type 3, as well as Kartagener syndrome, which are both diseases due to ciliary defects. [provided by RefSeq, Oct 2009]

DNAH5 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, ClinGen
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DNAH5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00802 (839/104582) while in subpopulation AFR AF = 0.0278 (783/28116). AF 95% confidence interval is 0.0262. There are 12 homozygotes in GnomAd4. There are 396 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH5	NM_001369.3 link	c.5272-17_5272-15dupTTT		intron_variant	Intron 32 of 78	ENST00000265104.5	NP_001360.1	Q8TE73

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5 link	c.5272-15_5272-14insTTT		intron_variant	Intron 32 of 78	1	NM_001369.3	ENSP00000265104.4		Q8TE73
DNAH5	ENST00000681290.1 link	c.5227-15_5227-14insTTT		intron_variant	Intron 32 of 78			ENSP00000505288.1		A0A7P0Z455

Frequencies

GnomAD3 genomes

AF:

0.00801

AC:

838

AN:

104588

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0278

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00276

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00319

Gnomad SAS

AF:

0.000371

Gnomad FIN

AF:

0.000529

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000274

Gnomad OTH

AF:

0.00360

GnomAD4 exome

AF:

0.00192

AC:

937

AN:

487352

Hom.:

Cov.:

AF XY:

0.00194

AC XY:

512

AN XY:

263412

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00640

AC:

AN:

12506

American (AMR)

AF:

0.00224

AC:

AN:

19166

Ashkenazi Jewish (ASJ)

AF:

0.00101

AC:

AN:

13854

East Asian (EAS)

AF:

0.00551

AC:

149

AN:

27028

South Asian (SAS)

AF:

0.00347

AC:

156

AN:

44982

European-Finnish (FIN)

AF:

0.00232

AC:

AN:

26734

Middle Eastern (MID)

AF:

0.000503

AC:

AN:

1988

European-Non Finnish (NFE)

AF:

0.00121

AC:

382

AN:

315748

Other (OTH)

AF:

0.00197

AC:

AN:

25346

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.324

Heterozygous variant carriers

121

181

242

302

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00802

AC:

839

AN:

104582

Hom.:

Cov.:

AF XY:

0.00838

AC XY:

396

AN XY:

47228

show subpopulations

African (AFR)

AF:

0.0278

AC:

783

AN:

28116

American (AMR)

AF:

0.00276

AC:

AN:

8696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2964

East Asian (EAS)

AF:

0.00320

AC:

AN:

3122

South Asian (SAS)

AF:

0.000371

AC:

AN:

2694

European-Finnish (FIN)

AF:

0.000529

AC:

AN:

1892

Middle Eastern (MID)

AF:

0.00

AC:

AN:

154

European-Non Finnish (NFE)

AF:

0.000274

AC:

AN:

54786

Other (OTH)

AF:

0.00359

AC:

AN:

1392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

132

165

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.62

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over